The present invention relates to a method and a composition for the treatment of skin disorders and, more particularly, to a method and a composition for the treatment and prevention of psoriasis, hypertrophic scars and keloids.
Keloids are benign fibrotic tumors which are believed to arise from the reticular dermis. They are characterized by increased tissue fibrosis and collagen deposition [Friedman, D. W. et al., J. Surg. Res., Vol. 55, p. 214-222, 1993]. Keloids usually first appear when a patient is between the ages of 10 and 30 years, and are often associated with trauma. They occur most commonly on the upper back, anterior chest, shoulders and ear lobes. Keloids are especially frequently seen in patients of African or Asian descent.
Hypertrophic scars are somewhat related to keloids, in that they are also characterized by increased tissue fibrosis and collagen deposition [Friedman, D. W. et al., J. Surg. Res., Vol. 55, p. 214-222, 1993]. Furthermore, hypertrophic scars are also most often seen in patients of African and Asian descent [Rockwell, W. B. et al., Plastic and Recon. Surg., Vol. 84, p 827-835, 1989]. Although there are certain differences between hypertrophic scars and keloids, such as a lower fibroblast density in keloids than in hypertrophic scars, a common mechanism is believed to underlie both conditions. Specifically, a genetically-determined aberration of the metabolism of melanocyte-stimulating hormone (MSH) is believed to be responsible for both hypertrophic scars and keloids [Rockwell, W. B. et al., Plastic and Recon. Surg., Vol. 84, p. 827-835, 1989]. Thus, both hypertrophic scars and keloids represent the effects of genetically abnormal behavior of skin cells.
Keloids and hypertrophic scars are characterized histologically by a rich vasculature, a high mesenchymal cell density, a thickened epidermis cell layer, and an abundance of collagen fibers. In hypertrophic scars, these fibers are loosely arrayed in a swirl-like pattern within bundles. In keloids, these fibers show even less organization, without any discrete bundles. By contrast, in normal skin these collagen fibers are arranged in distinct, clearly demarcated bundles.
The formation of both keloids and hypertrophic scars is marked by an initial infiltration of the traumatized tissue by fibroblasts, which is followed by the formation of a dense collagenous meshwork. Collagen production, as measured by prolyl hydroxylase activity, was found to be elevated in keloids, as compared to normal skin and normally healing wounds [Cohen, K. I. et al., Surg. Forum, Vol 22, p. 488, 1971]. Collagen synthesis was also found to be elevated in hypertrophic scars, but not to as great an extent [Rockwell, W. B. et al., Plastic and Recon. Surg., Vol. 84, p. 827-835, 1989]. The ratio of type I collagen to type III collagen was found to be significantly elevated in keloids but not hypertrophic scars, due to a specific increase in .alpha.1(I) collagen gene expression, although type III collagen gene expression is also increased [Friedman, D. W. et al., J. Surg. Res., Vol. 55, p. 214-222, 1993; Rockwell, W. B. et al., Plastic and Recon. Surg., Vol. 84, p. 827-835, 1989]. Thus, clearly the deposition of collagen plays an important role in keloid and hypertrophic scar formation.
Similarly, psoriasis is also characterized by genetically-determined abnormal behavior of skin cells. Psoriasis is clinically marked by extensive scaling and a thickened epidermis [G. D. Weinstein and J. L. McCullough, Cell Proliferation Kinetics, p. 327-342]. These clinical manifestations are caused by hyperproliferation of epidermal cells. This hyperproliferation is also seen in non-psoriatic skin of psoriatic patients, indicating that the genetic defect is also present in apparently "normal" skin cells of psoriatic patients [G. D. Weinstein and J. L. McCullough, Cell Proliferation Kinetics, p. 327-342]. Although collagen also plays a role in the etiology of psoriasis, the abnormal hyperproliferation of epidermal cells is linked to the increased deposition of a number of extracellular matrix components, including collagen. Thus, clearly the inhibition of these extracellular matrix components could be an important factor in the inhibition of hyperproliferation by genetically abnormal psoriatic cells.
Keloids, hypertrophic scars and psoriasis thus have a number of characteristics in common. First, they represent a significant cosmetic problem, particularly on the face where they can be highly disfiguring and a source of considerable distress to the patient. Second, they can also be a source of discomfort through pruritus and even pain. Indeed, both keloids and hypertrophic scars can become so large that they are crippling [D. D. Datubo-Brown, Brit. J. Plas. Surg., Vol 43, p. 70-77, 1990]. Furthermore, although keloids on the cornea are rare, they can potentially result in blindness [D. D. Datubo-Brown, Brit. J. Plas. Surg., Vol 43, p. 70-77, 1990). Third, collagen plays a crucial, if varied, role in the development of all three conditions. Finally, all three conditions are caused by a genetic defect in skin cells, which causes these cells to show abnormal behaviors.
Unfortunately, currently available treatments to inhibit the formation and growth of keloids and hypertrophic scars, and to treat psoriasis, are not completely successful. For example, surgery can be used to reduce the size or extent of the lesion, while physical pressure can be used to reduce the size and extent of keloids and hypertrophic scars, as well as to prevent their initial formation [D. D. Datubo-Brown, Brit. J. Plas. Surg., Vol 43, p. 70-77, 1990). However, neither treatment can prevent the lesion from recurring, and surgery especially carries a risk of increased morbidity.
Other forms of treatment include the administration of corticosteroids. For example, triamcinolone appears to reduce the size of keloids and hypertrophic scars by increasing the rate of collagen degradation [Rockwell, W. B. et al., Plastic and Recon. Surg., Vol. 84, p. 827-835, 1989]. However, the side effects of such medications are potentially dangerous and are not universally successful. Other treatments, such as radiation, also showed variable effectiveness and are associated with other potential side effects [Rockwell, W. B. et al., Plastic and Recon. Surg., Vol. 84, p. 827-835, 1989]. Thus, clearly improved treatments for keloids and hypertrophic scars are required.
As noted above, collagen synthesis and deposition plays an important role in keloid and hypertrophic scar formation, as well as in the cell hyperproliferation associated with psoriasis. The synthesis of collagen is also involved in a number of other pathological conditions, particularly those associated with primary or secondary fibrosis. The crucial role of collagen in fibrosis has prompted attempts to develop drugs that inhibit its accumulation [K. I. Kivirikko, Annals of Medicine, Vol. 25, pp. 113-126 (1993)].
Such drugs can act by modulating the synthesis of the procollagen polypeptide chains, or by inhibiting specific post-translational events, which will lead either to reduced formation of extra-cellular collagen fibers or to an accumulation of fibers with altered properties. Unfortunately, only a few inhibitors of collagen synthesis are available, despite the importance of this protein in sustaining tissue integrity and its involvement in various disorders.
For example, cytotoxic drugs have been used in an attempt to slow the proliferation of collagen-producing fibroblasts (J. A. Casas, et al., Ann. Rhem. Dis., Vol. 46, p. 763 (1987)], such as colchicine, which slows collagen secretion into the extracellular matrix [D. Kershenobich, et al., N. Engl. J. Med., Vol. 318, p. 1709 (1988)], as well as inhibitors of key collagen metabolism enzymes [K. Karvonen, et al., J. Biol Chem., Vol. 265, p. 8414 (1990); C. J. Cunliffe, et al., J. Med. Chem., Vol. 35, p.2652 (1992)].
Unfortunately, none of these inhibitors are collagen-type specific. Also, there are serious concerns about the toxic consequences of interfering with biosynthesis of other vital collagenous molecules, such as Clq in the classical complement pathway, acetylcholine esterase of the neuro-muscular junction endplate, conglutinin and pulmonary surfactant apoprotein.
Other drugs which can inhibit collagen synthesis, such as nifedipine and phenytoin, inhibit synthesis of other proteins as well, thereby non-specifically blocking the collagen biosynthetic pathway [T. Salo, et al., J. Oral Pathol. Med., Vol. 19, p. 404 (1990)].
Collagen cross-linking inhibitors, such as .beta.-amino-propionitrile, are also non-specific, although they can serve as useful anti-fibrotic agents. Their prolonged use causes lathritic syndrome and interferes with elastogenesis, since elastin, another fibrous connective tissue protein, is also cross-linking. In addition, the collagen cross-linking inhibitory effect is secondary, and collagen overproduction has to precede its degradation by collagenase. Thus, a type-specific inhibitor of the synthesis of collagen itself is clearly required as an anti-fibrotic agent.
Such a type-specific collagen synthesis inhibitor is disclosed in U.S. Pat. No. 5,449,678 for the treatment of fibrotic conditions. This specific inhibitor is a composition with a pharmaceutically effective amount of a pharmaceutically active compound of a formula: ##STR1##
wherein:
R.sub.1 is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl and lower alkoxy; PA1 R.sub.2 is a member of the group consisting of hydroxy, acetoxy and lower alkoxy, and PA1 R.sub.3 is a member of the group consisting of hydrogen and lower alkenoxy-carbonyl. PA1 R.sub.1 is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl, and lower alkoxy; PA1 R.sub.2 is a member of the group consisting of hydroxy, acetoxy, and lower alkoxy, and PA1 R.sub.3 is a member of the group consisting of hydrogen and lower alkenoxy. PA1 R.sub.1 is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl, and lower alkoxy; PA1 R.sub.2 is a member of the group consisting of hydroxy, acetoxy, and lower alkoxy and PA1 R.sub.3 is a member of the group consisting of hydrogen and lower alkenoxy. PA1 R.sub.1 is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl, and lower alkoxy; PA1 R.sub.2 is a member of the group consisting of hydroxy, acetoxy, and lower alkoxy, and PA1 R.sub.3 is a member of the group consisting of hydrogen and lower alkenoxy-carbonyl. PA1 R.sub.1 is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl, and lower alkoxy; PA1 R.sub.2 is a member of the group consisting of hydroxy, acetoxy, and lower alkoxy, and PA1 R.sub.3 is a member of the group consisting of hydrogen and lower alkenoxy-carbonyl. PA1 R.sub.1 is a member of the group consisting of hydrogen, halogen, nitro, benzo, lower alkyl, phenyl and lower alkoxy; PA1 R.sub.2 is a member of the group consisting of hydroxy, acetoxy and lower alkoxy, and PA1 R.sub.3 is a member of the group consisting of hydrogen and lower alkenoxy-carbonyl.
Of this group of compounds, Halofuginone has been found to be particularly effective for such treatment.
U.S. Pat. No. 5,449,678 discloses that these compounds are effective in the treatment of fibrotic conditions such as scleroderma and Graft Versus Host Disease. WO Patent No. 96/06616 further discloses that these compounds are effective treatments for restenosis by preventing the proliferation of vascular smooth muscle cells. The two former conditions are associated with excessive collagen deposition, which can be inhibited by Halofuginone. Restenosis is characterized by smooth muscle cell proliferation and extracellular matrix accumulation within the lumen of affected blood vessels in response to a vascular injury [Choi et al., Arch. Surg., Vol. 130, p. 257-261 (1995)]. One hallmark of such smooth muscle cell proliferation is a phenotypic alteration, from the normal contractile phenotype to a synthetic one. Type I collagen has been shown to support such a phenotypic alteration, which can be blocked by Halofuginone [Choi et al., Arch. Surg., Vol. 130, p. 257-261 (1995), WO Patent No. 96/06616]. Thus, Halofuginone can prevent such redifferentiation of smooth muscle cells after vascular injury by blocking the synthesis of type I collagen.
There is thus a widely recognized unmet medical need for an inhibitor of keloid and hypertrophic scar formation, as well as for a treatment of already formed keloids and hypertrophic scars, which have specific inhibitory effects.